Dysfunction of the cholinergic system and loss of synaptic pruning in the brain could induce progressive diminution in cognitive function, which is the main feature of neurodegenerative diseases, such as Alzheimer's disease1-3, and Parkinson's disease.4 Acetylcholine (ACh) is the primary neurotransmitter of cholinergic neurons in the central nervous system (CNS). Vesicular acetylcholine transporter (VAChT) is a neurotransmitter transporter which is responsible for loading ACh into secretory organelles in neurons making acetylcholine available for secretion.5,6 It is a reliable biomarker for assessing the status of cholinergic neurons in the central nervous system.7,8 Therefore, in vivo measurement of VAChT could provide a valuable understanding of the pathophysiology and diagnoses of these neurological disorders.
Positron emission tomography (PET) is a molecular imaging technique that produces a three-dimensional image of functional processes in the body and it is a sensitive and non-invasive method that can determine the biological activities of soft tissues. Currently, PET technique is used heavily in clinical oncology9-11, neuroimaging12,13, cardiology14, infectious15,16, and pharmacokinetics17.
There remains a need for improved diagnostic tools for assessing cholinergic neurons in vivo, including the ability to monitor the efficacy of cholinergic therapies in living patients. The development of suitable PET tracers to assess the loss of cholinergic neurons could provide useful information for monitoring the efficacy of cholinergic therapies in neurodegenerative diseases on a living subject.18 Vesicular acetylcholine transporter (VAChT) provides a reliable biomarker for cholinergic function in neurodegenerative diseases.
Currently, a number of radiotracers which were developed based on the structure of (−)-Vesamicol have been evaluated as VAChT imaging agents, such as (−)-[18F]FMV,19 (+)-[18F]FBT,20 (−)[11C]mABV,21 (−)-[18F]FEOBV,22 (−)-[11C]TZ659,23 and (−)-[18F]VAT.24 However, most of the radiotracers show unfavorable properties when applied to preclinical studies, such as poor extraction from blood, slow brain kinetics, and fast metabolism. Recently, (−)-[18F]FEOBV and (−)-[18F]VAT were reported for VAChT imaging in human studies.22,25 (−)-[18F]FEOBV offers advantages over single-photon emission computed tomography (SPECT) ligands for both preclinical and clinical imaging of cholinergic loss.22 (−)-[18F]VAT, which was developed and completed with rodents and NHP pre-clinical investigations by the inventors, was recently approved for the clinical research in human subjects.
A good radiotracer needs optimal pharmacokinetics before it can be applied on human subject. Thus, there remains a need for suitable VAChT PET tracers with improved pharmacokinetics.